A multifaceted study for the development of new antitumor nucleosides and nucleotides is proposed, which takes cognizance of the two fundamental requirements of current cancer chemotherapy, namely, the immediate need for new chemotherapeutic agents and the more long-range necessity for discovering metabolic sites in the cancer cell which may lend themselves to selective inhibition. The first objective is approached through the preparation of new nucleoside and nucleotide analogs, and through the study of their antitumor activity, their pharmacological properties and their modes of action. This aim also includes studies on the mechanism by which natural metabolites can enhance the antitumor effect of these analogs, while preventing their toxicity to the host. The second goal is implemented through comparative studies concerning the metabolism and function of the cyclic pyrimidine nucleotides in normal tumor cells. This objective involves the isolation and characterization of enzymes participating in the synthesis and metabolism of the cyclic nucleotides, and studies concerning the function of these metabolities in the intact cell, particularly as it relates to the control of protein phosphorylation required for selective gene expression.